(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1(pyrrolidinocarbonyl)-ethyl]-benzimidazole, the monohydrochloride thereof, preparation thereof and the use as pharmaceutical composition

ABSTRACT

Crystalline forms of the compounds (R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1 -(carboxymethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole and the monohydrochloride thereof, processes for the preparation thereof and the use thereof as pharmaceutical compositions.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. patent applicationSer. No.10/463,033 filed Jun. 17, 2003, which claims the benefit of U.S.Provisional Application Ser. No. 60/395,188, filed on Jul. 11, 2002; theentire disclosures of which are hereby incorporated by reference intheir entirety.

FIELD OF THE INVENTION

The present invention relates to the crystalline forms of the compounds(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazoleand the monohydrochloride thereof, processes for the preparation thereofand the use thereof as pharmaceutical compositions.

BACKGROUND TO THE INVENTION

A number of benzimidazole derivatives are known in the prior art. Thus,for example, International Patent Application WO 00/01704 disclosesbenzimidazole derivatives which have valuable pharmacologicalproperties, particularly an antithrombotic activity, which is based, forexample, on a thrombin-inhibiting or factor Xa-inhibiting activity.

By virtue of their pharmacological properties, the compounds(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazoleand the monohydrochloride thereof may be used for the prevention andtreatment of venous thromboses in various vascular areas, including deepand superficial leg vein thromboses, vena cava thromboses, thromboses ofthe renal and hepatic veins including veno-occlusive disease, for theprevention and treatment of pulmonary embolism, for the treatment ofpatients with all forms of coronary heart disease, including the acuteform, as unstable angina pectoris or acute myocardial infarct, and thechronic form, as stable angina pectoris, or in patients withpost-myocardial infarct condition, for preventing acute and chronicreocclusions after bypass operations on all vascular areas and afterangioplasty (PT(C)A), and for preventing occlusion in patients withperipheral arterial diseases, for treating stroke in its acute form, inthe chronic form in patients with post-stroke conditions and for primaryprophylaxis in patients with stenoses of the afferent cerebral arteries.

The benzimidazoles mentioned above may also be used to treat patients onkidney replacement therapy. This comprises both anticoagulation duringthe use of kidney replacement therapy to keep the system open and alsotreatment of the system activation of clotting such as occurs inpatients on kidney replacement therapy, both in patients undergoingchronic haemodialysis and in those undergoing a process of veno-venousor arterio-venous chronic filtration. Accordingly, both patients withchronic kidney failure and patients with acute kidney failure may betreated irrespective of the cause of the kidney failure. This alsoincludes the prevention and treatment of blockage of the dialysis shunt.

The abovementioned pharmacologically valuable properties of thebenzimidazole derivatives disclosed in the prior art constitute thebasic prerequisite for effective use of the compounds as pharmaceuticalcompositions. However, to be permitted for use as a medicament, anactive substance must also satisfy further requirements. Theseparameters are largely to do with the physicochemical nature of theactive substance.

Without being restrictive, examples of these parameters are thestability of effect of the starting substance under variousenvironmental conditions, the stability during production of thepharmaceutical formulation and stability in the final compositions ofthe drug. The pharmaceutically active substance used to prepare thepharmaceutical compositions should therefore have great stability whichis ensured even under all kinds of environmental conditions. This isabsolutely essential to prevent pharmaceutical compositions being usedwhich contain breakdown products, for example, in addition to the activesubstance itself. In such a case the content of active substance presentin the pharmaceutical formulation might be lower than specified.

The absorption of moisture reduces the content of pharmaceuticallyactive substance as a result of the increased weight caused by theuptake of water. Pharmaceutical compositions with a tendency to absorbmoisture have to be protected from moisture during storage, e.g. by theaddition of suitable drying agents or by storing the drug in anenvironment where it is protected from moisture. In addition, the uptakeof moisture may reduce the content of pharmaceutically active substanceduring manufacture if the pharmaceutical substance is exposed to theenvironment without being protected from moisture in any way.Preferably, therefore, a pharmaceutically active substance should beonly slightly hygroscopic.

As the crystal modification of an active substance is important to thereproducible active substance content of a preparation, there is a needto clarify as far as possible any existing polymorphism of an activesubstance present in crystalline form. If there are differentpolymorphism modifications of an active substance care must be taken toensure that the crystalline modification of the substance does notchange in the pharmaceutical preparation later produced from it.Otherwise, this could have a harmful effect on the reproducible potencyof the drug. Against this background, active substances characterised byonly slight polymorphism are preferred.

Another criterion which may be of exceptional importance under certaincircumstances depending on the choice of formulation or the choice ofmanufacturing process is the solubility of the active substance. If forexample pharmaceutical solutions are prepared (e.g. for infusions) it isessential that the active substance should be sufficiently soluble inphysiologically acceptable solvents. It is also very important for drugswhich are to be taken orally that the active substance should besufficiently soluble.

The problem of the present invention is to provide a pharmaceuticallyactive substance which not only is characterised by high pharmacologicalpotency but also satisfies the above-mentioned physicochemicalrequirements as far as possible.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the x-ray powder diffractogram of the crystallinemonohydrochloride of the compound(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole.

FIG. 2 shows the x-ray powder diffractogram of the crystalline compound(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-(pyrrolidino-carbonyl)-ethyl]-benzimidazole.

DETAILED DESCRIPTION OF THE INVENTION

Surprisingly, it has been found that the problem outlined above issolved by the crystalline monohydrochloride of the compound(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazoleof formula (I):

The monohydrochloride according to the invention is characterised by ahigh degree of stability and dissolves very easily in physiologicallyacceptable solvents.

The crystalline form of the monohydrochloride of the compound(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-(pyrrolidino-carbonyl)-ethyl]according to the invention is characterised by a melting point ofT_(m.p.)=222° C.±5° C. (determined by DSC=Differential ScanningCalorimetry; evaluated by the onset; heating rate: 10° C./min). Thevalue given was determined using a DSC 821 made by Messrs MettlerToledo.

Therefore a first object of the present invention is the crystallinemonohydrochloride of the compound(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole,characterised by a melting point of T_(m.p.)=222° C.±5° C.

The crystalline form of the(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazolemonohydrochloride according to the invention was examined more closelyby X-ray powder diffraction. The diagram obtained is shown in FIG. 1.

Table 1that follows summarises the data obtained in this analysis: TABLE1 X-ray powder reflections and intensities (standardised) of (R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-(pyrrolidino-carbonyl)-ethyl]-benzimidazole-monohydrochloride. 2 Θd_(hkl) intensity [°] [Å] I/I_(o) [%] 9.17 9.64 13 10.21 8.66 19 11.287.84 21 13.06 6.77 11 13.34 6.63 16 14.03 6.31 100 14.57 6.07 38 15.625.67 23 17.22 5.14 34 18.45 4.80 14 18.63 4.76 16 19.19 4.62 16 19.784.48 13 20.45 4.34 14 20.99 4.23 12 21.24 4.18 17 22.39 3.97 14 22.663.92 12 23.50 3.78 15 23.90 3.72 30 24.22 3.67 18 24.51 3.63 16 25.333.51 19 25.63 3.47 16 26.04 3.42 9 27.83 3.20 12 29.76 3.00 10 31.102.87 12 32.39 2.76 8 32.98 2.71 11 33.32 2.69 12 33.89 2.64 10 35.732.51 9 36.34 2.47 8

In Table 1above the value “2 Θ[°]” denotes the angle of diffraction indegrees and the value “d_(hkl)[Å]” denotes the specified distances in Åbetween the lattice planes.

The x-ray powder diagram was recorded, within the scope of the presentinvention, using a Bruker D8 Advanced Diffractometer fitted with alocation-sensitive detector (OED) and a Cu anode as the x-ray source(CuK_(α) radiation, λ=1.5418 Å, 30 kV, 40 mA).

According to the findings shown in Table 1the present invention relatesto crystalline(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-monohydrochloride,characterised in that in the x-ray powder diagram it has, inter alia,the characteristic values d=6.31 Å, 6.07 Å, 5.14 Å and 3.72 Å.

The crystalline monohydrochloride of the compound(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-(pyrrolidinocarbo-nyl)-ethyl]-benzimidazoleaccording to the invention occurs in the form of hydrates which,depending on the relative humidity, contain between about 3.0% and 6.5%water. By virtue of its structure the compound is capable of absorbingwater of crystallisation and releasing it again without the crystallinestructure changing fundamentally.

Moreover, the monohydrochloride according to the invention formssolvates with organic solvents, e.g. with ethanol.

A second object of the present invention is a process for preparing thecrystalline salt(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-monohydrochlorideaccording to the invention, comprising the following steps:

Step (a):

The starting material used is the(R)-2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-amino-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazoleof formula (II) already described in WO 00/01704:

The free primary amino group is alkylated for example with 1 to 1.5equivalents, preferably with about 1.2 equivalents, of a compound ofgeneral formula

wherein R denotes a C₁₋₃-alkyl group and X denotes a leaving group, forexample a halogen atom such as the chlorine, bromine or iodine atom, thep-toluenesulphonyl or methanesulphonyl group, of which ethylbromoacetate or n-propyl bromoacetate is preferably used, in an organicsolvent or mixture of solvents, in the presence of a base. Suitablesolvents according to the invention include ethyl acetate, n-propylacetate, N-methylpyrrolidinone, dimethylformamide, dimethylacetamide ormixtures thereof. According to the invention, a solvent mixtureconsisting of N-methylpyrrolidinone and ethyl acetate or n-propylacetate is used. Suitable bases include for example tertiary amines suchas diisopropylethylamine (Hünig base) or triethylamine in an amount of 1to 2.5 equivalents. The reaction is preferably carried out attemperatures between 0° C. and the boiling temperature of the solventmixture, e.g. between 0° C. and 150° C., preferably between 10° C. and30° C.

Purification of the reaction mixture through aqueous extractions yields,after partial evaporation of the organic solvent, a concentratedsolution of crude(R)-2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-(n-C₁₋₃-alkyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazoleof general formula

wherein R denotes a C₁₋₃-alkyl group.

Step (b):

The concentrated solution of the crude compound of formula (IV) obtainedin step (b) is dissolved in a C₁₋₃-alcohol as solvent and reacted bypiping in hydrogen chloride gas, with cooling, preferably at atemperature below about 20° C., to produce the imino ester asintermediate. According to the invention methanol, ethanol or n-propanolis preferably used as alcohol, while the choice of solvent depends onthe ester of formula (IV) used. Once all the hydrogen chloride gas hasbeen piped in the reaction mixture is stirred until the reaction iscomplete at a temperature between 0° C. and 30° C., preferably at about20° C.

The conversion of the iminoester into an amidine of general formula

wherein R denotes a C₁₋₃-alkyl group,

is carried out with cooling, preferably at temperatures between 0° C.and 40° C., most preferably at 15° C. to 40° C., by reacting with anaqueous ammonia solution in a C₁₋₃-alcohol, preferably methanol, ethanolor n-propanol. Once the reaction has ended, to obtain the amidine,ammonium chloride may be filtered off optionally after partialdistillation of the solvent. The compound (V) may be intermediatelyisolated in the form of the hydrochloride or directly as thep-toluenesulphonic acid salts of general formula (VI) (cf. step c).

Step (c):

The intermediate compounds(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(n-C₁₋₃-alkyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazoleof general formula (V) are precipitated according to the invention inthe form of sulphonic acid salts, for example in the form of benzene-,p-toluene-, p-chlorobenzene-, 1- or 2-naphthenesulphonic acid salts,most preferably in the form of the the p-toluenesulphonic acid salts ofgeneral formula (VI)

wherein R denotes a C₁₋₃-alkyl group, enabling the compound to be easilyisolated from the aqueous medium.

Further purification of the p-toluenesulphonic acid salts of thecompounds of general formula (VI) is carried out by pH-controlleddissolving and precipitation of the salt in aqueous medium or bysuspending in water.

Step (d):

In order to prepare the free base(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazoleof formula

the corresponding p-toluenesulphonic acid salt of general formula (VI)is dissolved in a suitable organic solvent. Suitable solvents includefor example alcohols such as methanol, ethanol, i-propanol or polarsolvents such as N-methylpyrrolidinone or dimethylformamide, preferablymethanol or ethanol.

Then 1.5 to 3 equivalents, preferably 2 to 2.5 equivalents of a suitablebase are added to this solution. Suitable bases within the scope of thepresent invention include sodium hydroxide, potassium hydroxide, lithiumhydroxide and barium hydroxide.

The reaction mixture can then be heated and in this way the progress ofthe reaction can be speeded up. Preferably, the reaction mixture isheated, with thorough mixing, to a temperature above 30° C., the maximumtemperature which can be selected depending on the boiling temperatureof the solvent used, preferably at temperatures between 30° C. and 80°C.

Then 0.5 to 2 equivalents, preferably 1 to 1.5 equivalents, of an acid,preferably p-toluenesulphonic acid, are added.

If sodium hydroxide is used as the base, the desired product of formula(VIl) is obtained directly on crystallisation. If potassium hydroxide isused as base, the potassium salt of p-toluenesulphonic acid crystallisesout first. Then the desired product of formula (VIl) can becrystallised.

Step (e):

In order to prepare the crystalline monohydrochloride of general formula(I) according to the invention the base (VII) obtained in step (d) issuspended or dissolved in a suitable organic solvent or mixture ofsolvents. Particularly preferred solvents according to the inventioninclude methanol, ethanol, n-propanol, i-propanol, acetone,dimethylformamide or N-methylpyrrolidinone. A certain amount of watermay be added as cosolvent.

Then the reaction mixture is heated to a temperature between 20° C. andthe reflux temperature of the solvent, preferably between 30° C. and 80°C. According to the invention, hydrogen chloride dissolved in an organicsolvent or hydrochloric acid is added to the solution or suspension.

According to the invention 0.8 to 1.2 mol, preferably about 1 mol, ofhydrogen chloride are added per mol of base used. After the acid hasbeen added the suspension is cooled to a temperature between 0° C. and40° C., preferably between 20° C. and 25° C. and the product is filteredoff.

A third object of the invention relates to crystalline(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-(pyrrolidinocarbo-nyl)-ethyl]-benzimidazole-monohydrochloride,obtainable by the process described herein before.

A fourth object of the invention is the use of the crystallinemonohydrochloride of the compound(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazoleaccording to the invention as a pharmaceutical composition on account ofits pharmaceutical activity.

The p-toluenesulphonic acid salts of general formula (VI) obtained asintermediates in the process described above are valuable intermediateproducts for preparing the crystalline(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-monohydrochlorideof formula (I).

A fifth object of the present invention thus consists of thep-toluenesulphonic acid salts of general formula (VI):

-   (1)    (R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(methyloxycarbonylmethyl-amino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-p-toluenesulphonate,-   (2) (R)-2-(4-amidinophenylaminomethyl)-1-methyl    -5-[1-(ethyloxycarbonylmethyl-amino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-p-toluenesulphonate    and-   (3)    (R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(n-propyloxycarbonyl-methylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-p-toluenesulphonate.

The crystalline form of the free base(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazoleis the direct precursor for preparing the monohydrochloride of formula(I) and also has the pharmacological activity described hereinbefore.

A sixth object of the present invention is therefore the crystallineform of the free base(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole,characterised by a melting point T_(m.p.)=241° C.±5° C. (determined byDSC=Differential Scanning Calorimetry; evaluated by the onset; heatingrate: 10° C./min). The value given was determined using a DSC 821 madeby Messrs Mettler Toledo.

The crystalline form of the free base(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazoleaccording to the invention was investigated in more detail by x-raypowder diffraction. The diagram obtained is shown in FIG. 2.

Table 2 which follows summarises the data obtained in this analysis:TABLE 2 X-ray powder reflections and intensities (standardised) of(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-(pyrrolidino-carbonyl)-ethyl]-benzimidazole. 2 Θ d_(hkl) intensity [°][Å] I/I_(o) [%] 7.331 12.04817 11.9 10.804 8.18223 7.5 11.572 7.6409312.3 12.312 7.18300 4.2 12.976 6.81712 7.6 13.726 6.44632 5.9 14.2956.19076 17.9 14.726 6.01067 100.0 15.365 5.76201 6.7 17.168 5.16080 29.418.014 4.92041 11.3 18.309 4.84161 9.2 19.168 4.62671 7.1 20.224 4.387448.8 21.500 4.12969 15.8 22.240 3.99395 7.9 23.308 3.81335 19.4 23.7383.74525 9.4 24.308 3.65862 8.2 24.890 3.57442 8.3 25.131 3.54076 7.926.503 3.36044 4.7 27.204 3.27547 7.3 27.786 3.20815 9.6 28.530 3.126087.5 29.678 3.00774 6.3 30.962 2.88589 5.0 32.412 2.76004 4.3

In Table 1 above the value “2 0 Θ[°]” denotes the angle of diffractionin degrees and the value “d_(hkl) [Å]” denotes the specified distancesin Å between the lattice planes.

The x-ray powder diagram was recorded, within the scope of the presentinvention, using a Bruker D8 Advanced-diffractometer fitted with alocation-sensitive detector (OED) and a Cu anode as the x-ray source(CuK_(α)radiation, λ=1.5418 Å, 30 kV, 40 mA).

According to the findings shown in Table 2 the present invention relatesto crystalline(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole,characterised in that in the x-ray powder diagram it has, inter alia,the characteristic values d=6.19 Å, 6.01 Å, 5.16 Å, 4.13 Åand 3.81 Å.

The invention further relates to the use of the crystalline base(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-(pyrrolidi-nocarbonyl)-ethyl]-benzimidazoleaccording to the invention as a pharmaceutical composition on account ofits pharmaceutical activity. Solid stress stability data of the freebase and of the corresponding monohydrochloride Stress Storage StressStorage Parameters method conditions time monohydrochloride Free basetemperature open glass 105° C. 24 hours no decomposition approx. 1% dishdecomposition temperature open glass  70° C.; approx. 3 days nodecomposition approx. 4% and relative dish 90% relative decompositionhumidity humidity Light open glass Suntester 22-24 hours no significantapprox. 1% dish xenon lamp decomposition decomposition (<1%)Experimental section

The HPLC data given below were measured under the following parameters,unless otherwise stated:

Column: Prontosil 120-5-C18AQ, 5 μm, 125×4 mm; solvent A: 0.2% aqueousKH₂PO₄ solution, adjusted to pH=5.5 with 1M NaOH; solvent B:acetonitrile; column temperature: 45° C.; flow: 1 mL/min; gradientsystem: up to 2 min 10% solvent B; within 14 min gradient to 60% solventB, within 4 min gradient to 80% solvent B; concentration of the samplesolution: 2 mg/mL in acetonitrile/water=7:3; injection volume: 1 μL;detection at 220 nm.

EXAMPLE 1(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(n-propyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-p-toluenesulphonicacid salt

442 g (2.09 mol) of n-propyl bromoacetate are poured into a solution of700 g (1.74 mol) of (R)-2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-amino-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole and 700 mL ofdiisopropylethylamine in 1.4 L of N-methylpyrrolidinone and 1.4 L ofn-propylacetate within 15 minutes at 20° C. The reaction mixture isstirred for 14 hours at 20° C. 2.1 L of n-propylacetate and 5.6 L ofwater are added. The mixture is cooled to 20° C. and the aqueous phaseis separated off. 3.5 L of water are added to the organic phase and thisis adjusted to a pH of pH=5.8 by the addition of 30% hydrochloric acid.The aqueous phase is separated off. 3.5 L of water and 105 g of sodiumchloride are added to the organic phase with stirring. The aqueous phaseis separated off. The organic phase is concentrated by evaporation underreduced pressure using the rotary evaporator. 0.9 L of n-propylacetateand 3.5 L of n-propanol are added to the resulting oil. Another 3 litresof solvent are distilled off under reduced pressure.

3.5 L n-propanol are added to the residue and cooled to −15° C. 1.92 kgof hydrogen chloride gas are piped through this solution so that thetemperature does not exceed 8° C. After the introduction of gas hasended the reaction mixture is stirred for 20 hours at 20° C. Then thereaction solution is cooled to 10° C. The reaction solution is stirredinto a solution of 4.53 L of a 25% aqueous ammonia solution in 7 L ofn-propanol cooled to −20° C., while the temperature is kept below 20° C.The reaction mixture is stirred for 16 hours at 24° C. 5.8 L of solventare distilled off under reduced pressure. The reaction mixture is cooledto 45° C. and filtered through a pressure filter. The pressure filter iswashed with 3.5 L of hot n-propanol. 8.8 L of solvent are distilled offfrom the filtrate in a rotary evaporator under reduced pressure. Theresidue remaining is suspended with 7 L acetone while heating andrefluxing. The suspension is cooled to 0° C. and stirred for one hour atthis temperature. The suspension is suction filtered and washed with 2.8L acetone. The filter cake is dried at 50° C. in the circulating airdrier. 1.23 kg of(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(n-propyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-hydro-chlorideare obtained

HPLC: R_(f)=9.9 min (product)

 R_(f)=12.9 min (bisalkylated by-product)

Precipitation as p-toluenesulphonic acid salt:

1.22 kg of the crude hydrochloride described above are dissolved withstirring in 1.05 L n-propanol and 5.6 L water by heating to 55° C. Tothis solution is added a solution of 530 g of p-toluenesulphonic acidmonohydrate and 146 mL of a 50% sodium hydroxide solution in 4.2 L ofwater. The resulting mixture is cooled to 0° C. and stirred for 30minutes at this temperature. The suspension is suction filtered andwashed with 3.5 L of water. The filter cake is dried in the circulatingair drier at 50° C. 0.70 kg of the p-toluenesulphonic acid salt of thetitle compound are obtained as a crude product.

HPLC: R_(f)=3.6 min (p-toluenesulphonic acid)

 R_(f)=9.9 min (product)

 R_(f)=12.9 min (bisalkylated by-product)

A further 0.19 kg of product are isolated from the mother liquor byadjusting the pH to pH=7.5 with 25% ammonia solution.

Total yield: 0.89 kg. (73% of theory)

Further Purification of the p-toluenesulphonic acid salt:

kg of the crude product of the p-toluenesulphonic acid salt describedabove are suspended in 13.2 L water at 20° C. 151 g ofp-toluenesulphonic acid and 328 mL of 30% hydrochloric acid are added,whereupon the solid goes into solution and a pH of 1 to 1.5 is obtained.The pH is adjusted to 4 by the addition of 25% ammonia solution (approx.170 mL). The resulting suspension is stirred for 19 hours at 20° C. Theprecipitate (bisalkylated by-product) is filtered off. The filter cakeis washed with 2.2 L water. 1.54 L of n-propanol are added to thefiltrate followed by 130 mL of 25% ammonia solution. The suspension isstirred overnight at 20° C. The precipitate is suction filtered andwashed with 3.3 L water. The filter cake is dried at 50° C. in thecirculating air drier. 0.83 kg (76% of theory) of the title compound areobtained.

HPLC: R_(f)=3.6 min (p-toluenesulphonic acid)

 R_(f)=9.9 min (product)

EXAMPLE 2 Method of preparing the free base by ester cleaving withsodium hydroxide starting from the p-toluenesulphonic acid salt of then-propyl ester

-   (R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-(pyrroli-dinocarbonyl)-ethyl]-benzimidazole

To a solution of 27.7 g (40 mmol) of(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(n-propyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-p-toluenesulphonatein 134 mL of methanol are added 3.36 g (84 mmol) of solid sodiumhydroxide and the mixture is refluxed for 3 hours. 8.37 g (44 mmol) ofp-toluenesulphonic acid hydrate are added and the mixture is refluxedfor a further 1.5 hours. The solution is allowed to cool to 40° C. andfiltered (clear filtration). 170 mL methanol are added to the filtrateand it is inoculated. The suspension formed is stirred overnight at 20°C. The suspension is suction filtered and the filter cake is washed with60 mL methanol. The product is dried in the circulating air drier at 40°C. The title compound is obtained as a crystalline solid.

Yield: 13.8 g. (72% of theory) melting point: T_(m.p.)=249° C.±5° C.(decomposition, DSC, evaluating using onset, heating rate: 10° C./min ).

EXAMPLE 3 Method of preparing the free base by ester cleaving withsodium hydroxide starting from the hydrochloride salt of the n-propylester

-   (R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-(pyrroli-dinocarbonyl)-ethyl]-benzimidazole

To a solution of 93.9 g (0.15 mol) of(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(n-propyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-hydrochloride×1equivalentn-propanol in 470 mL methanol are added 13.3 g (0.33 mol) of solidsodium hydroxide and this mixture is refluxed for 1.5 hours under aninert gas atmosphere. It is allowed to cool to 50° C. and within 10minutes 22.8 mL (0.18 mmol) of chlorotrimethylsilan are added dropwisethereto. The mixture is diluted with 470 mL of dimethylsulphoxide and370 mL of methanol are distilled off at 300 mbar/80° C. To eliminatesodium chloride the suspension is filtered hot. The filtrate is cooledto 20° C. and stirred for 3 hours at 20° C. The suspension formed issuction filtered and the filter cake is washed with 50 mLdimethylsulphoxide and 100 mL acetone. The filter cake is dried at 50°C. in the circulating air drier. The title compound is obtained as acolourless solid.

Yield: 58.8 g. (81% of theory).

For further purification the product thus obtained may be crystallisedfrom methanol.

melting point: T_(m.p.)=241° C.±5° C. (decomposition, DSC, evaluated viaonset, heating rate: 10° C./min).

EXAMPLE 4 Method of precipitating the monohydrochloride from the freebase

-   (R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-(pyrroli-dinocarbonyl)-ethyl]-benzimidazole-monohydrochloride

A suspension of 11 g (23 mmol) of(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazolein 88 mL methanol is heated to 35° C. to 40° C. To this suspension areadded 8.4 mL of a 2.75 molar solution of hydrogen chloride (23 mmol) inethyl acetate. The starting material is dissolved and the hydrochloridebegins to crystallise out. The suspension is cooled to 20° C. andsuction filtered. The filter cake is dried in the vacuum drying cupboardat 35° C. 9.2 g (78% of theory) of the title compound are obtained as acrystalline solid.

To eliminate traces of methanol 8 g of the title compound obtained aboveare suspended in 80 mL of ethanol and stirred for 30 minutes at 50° C.The suspension is cooled to 20° C. and suction filtered. The filter cakeis washed with ethanol and dried in the vacuum drying cupboard at 35° C.

Yield: 7.3 g. (91% of theory based on hydrochloride used) melting point:T_(m.p.)=222° C.±5° C. (decomposition, DSC, evaluated via onset, heatingrate: 10° C./min).

EXAMPLE 5

-   (R)-2-(4-Amidinophenylaminomethyl)-1-methyl-5-[1-(ethyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-p-toluenesulphonic    acid salt

4.22 kg (10.5 mol) of(R)-2-(4-cyanophenylaminomethyl)-1-methyl-5-[1-amino-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazoleand 3.11 kg (24.1 mol) of diisopropylethylamine are dissolved in amixture of 8.4 L of N-methylpyrrolidinone and 8.4 L of ethylacetate. 2.1kg (12.6 mol) of ethyl bromoacetate are metered in and the mixture isstirred for 15 hours at 20° C. 34 L of water are added. The aqueousphase is separated off. 21 L of water are added to the organic phase andthe pH is adjusted to 5.7 by the addition of hydrochloric acid (30%).The aqueous phase is separated off and the organic phase is washed witha solution of 0.42 kg of sodium chloride in 21 L of water. The organicphase is concentrated under reduced pressure (10.6 L of ethyl acetateare distilled off). The concentrate is diluted with 42 L of ethanol andconcentrated again under reduced pressure (21 L are distilled off). At20° C. 15 kg (411 mol) of hydrochloric acid gas are piped into theresulting solution and it is stirred at 20° C. until the reaction iscomplete (the reaction to obtain the iminoester is monitored by HPLC).The iminoester solution formed is diluted with 25 L of ethanol. 37.8 kg(555 mol) of ammonia solution (25%) are added to the solution so thatthe temperature does not exceed 40° C. The solution is then stirred for2 hours. The ammonium chloride formed is filtered through a pressurefilter and the filtered material is washed with 30 L of ethanol. 42 L ofethanol are distilled off from the filtrate under reduced pressure. Asolution of 3.86 kg (20.3 mol) of p-toluenesulphonic acid monohydrate in17 L of water is added to the filtrate. Another 20 L of water are added.The pH is adjusted to 8.0 with sodium hydroxide solution (50%). Theremaining ethanol is distilled off under reduced pressure. Towards theend of the distillation the product crystallises out. The pH is adjustedto 7.5 with sodium hydroxide solution (50%) and the suspension formed iscooled to 3° C. The product is centrifuged off and washed with 13 L ofwater. The product is dried in the drying cupboard at 50° C. 4.89 kg(69% of theory) of the title compound are obtained in the form of thecrude product.

Further purification of the p-toluenesulphonic acid salt:

4.75 kg of the crude product are suspended in 38 L of water. Thesuspension is stirred for 2.5 hours at 20° C. The suspension iscentrifuged off and washed with 19 L of water. The product is dried at50° C. in the drying cupboard.

-   3.86 kg (81 % of theory) of the title compound are obtained.-   HPLC: R_(f)=3.6 min (p-toluenesulphonic acid)-   R_(f)=17.6 min (product)

Column: Inertsil ODS-2, 5 μm, 125×4.6 mm; solvent A: 0.3% aqueous KH₂PO₄solution, adjusted to pH=5.0 with 1M NaOH; solvent B: acetonitrile;column temperature: 45° C.; flow: 1 mL/min; gradient system: start: 10%solvent B; within 20 min gradient to 25% solvent B, within 10 mingradient to 50% solvent B; concentration of the sample solution: 2 mg/mLin acetonitrile/water=7:3; injection volume: 3 μL; detection at 217 nm.

EXAMPLE 6 Method of preparing the free base by ester cleaving withpotassium hydroxide starting from the p-toluenesulphonic acid salt ofthe ethyl ester

-   (R)-2-(4-Amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-(pyrroli-dinocarbonyl)-ethyl]-benzimidazole

3.7 kg (5.49 mol) of(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazol-p-toluenesulphonicacid salt are dissolved in 7.4 L of methanol at 40° C. To this solutionis added a solution of 0.795 kg (12.8 mol) of potassium hydroxide powderin 5.6 L of methanol und this is then rinsed with 1.8 L of methanol. Themixture is stirred for 2.5 hours at 40° C. The potassium salt of thep-toluenesulphonic acid crystallises out. A solution of 1.37 kg (7.2mol) of p-toluenesulphonic acid monohydrate in 2.8 L of methanol isadded to the suspension, this is rinsed with 1.8 litres of methanol andcooled to 22° C. The precipitated potassium salt of p-toluenesulphonicacid is separated off using a pressure filter and the filter cake iswashed with 7.4 litres of methanol. The filtrate is inoculated with thetitle compound and stirred overnight. The precipitated product issuction filtered under argon, washed with 3.7 L of methanol and recycledinto the reactor while still damp. 18.5 L of methanol are added and thesuspension is refluxed for one hour and cooled to 22° C. The product issuction filtered under argon, washed with 3.7 L of methanol and dried at30° C. in a circulating air drier.

2.22 kg (85% of theory) of the title compound are obtained.

Melting point: T_(m.p.)=241° C.±5° C. (decomposition, DSC, evaluatedusing onset, heating rate: 10° C./min, measured with DSC 204 of MessrsNetzsch-Gerätebau GmbH).

EXAMPLE 7 Method of precipitating the monohydrochloride from ethanol

-   (R)-2-(4-Amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-(pyrroli-dinocarbonyl)-ethyl]-benzimidazole-monohydrochloride

5.0 g of(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazoleare refluxed in 25 mL of ethanol. After the addition of 2 mL of water asolution is obtained. The solution is filtered clear and the filter isrinsed with 25 mL of ethanol. The filtrate is heated to 70° C. Asolution of 0.802 mL of conc. hydrochloric acid in 25 mL of ethanol isadded and then another 25 mL of ethanol are added. The mixture is cooledto 25° C. and stirred for one hour at this temperature. The product isfiltered off, washed with 15 mL of ethanol and dried in the circulatingair drier. 4.95 g (92% of theory) of the title compound are obtained asa crystalline solid

Melting point: T_(m.p.)=220° C.±5° C. (decomposition, DSC, evaluatingusing onset, heating rate: 10° C./min ).

1-2. (canceled)
 3. A process for preparing(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole-monohydrochloride,comprising the following steps: (a) alkylating the free amino group ofthe compound(R)-2-(4-cyanophenylamino-methyl)-1-methyl-5-[1-amino-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazoleof the formula (II):

 with a compound of the formula III

 wherein R denotes a C₁₋₃-alkyl group and X denotes a leaving group,thereby obtaining a compound of general formula

 wherein R denotes a C₁₋₃-alkyl group; (b) converting the compound ofthe formula (IV) obtained in (a) into an amidine of the formula V

 wherein R denotes a C₁₋₃-alkyl group; (c) precipitating an intermediatecompound of the formula (V) as the p-toluenesulphonic acid salt of theformula VI

 wherein R denotes a C₁₋₃-alkyl group; (d) converting a compoundobtained according to (c) into the base (VII) and subsequentlyprecipitating the free base(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazoleof formula VII

 and (e) precipitating the monohydrochloride of the formula (I) bysuspending the base obtained in (d) in a solvent or mixture of solvents,optionally heating the reaction mixture to a temperature between 20° C.and the reflux temperature of the solvent or mixture of solvents andadding hydrogen chloride.
 4. (canceled)
 5. A p-toluenesulphonic acidsalt of the formula VI

wherein R denotes a C₁₋₃-alkyl group. 6-8. (canceled)